The most common form of heart disease is myocardial ischemia, which is characterized by an insufficient[unreadable] supply of blood, substrates and oxygen to the heart due to coronary artery obstruction. If not treated,[unreadable] irreversible damage ensues in the form of myocardial infarction (heart attack). The overall aim of the Project[unreadable] is to identify mechanisms which are fundamental to the understanding of ischemic heart disease, which will[unreadable] be accomplished by utilizing an integrative approach including cellular and molecular studies as well as[unreadable] integrative whole animal physiology. Project 1 involves the study of the mechanisms of cardiac protection in[unreadable] the second window of ischemic protection (SWOP) in chronically instrumented conscious swine. One unique[unreadable] aspect of this Project is the use of the large mammalian model, which resembles pathophysiology in humans[unreadable] more closely than rodents, lacks preformed coronary collateral vessels, and the heart is sufficiently large to[unreadable] provide measurements of regional function, blood flow, biochemistry, molecular biology and pathology from[unreadable] the same animals in both the ischemic zone and a contralateral, remote, non-ischemic zone. The project is[unreadable] based, in part, on the novel observation that either regional cardiac denervation or adrenergic receptor[unreadable] blockade abrogates the second window of protection. There are three major hypotheses: A)SWOP is[unreadable] critically dependent on the sympathetic nervous system; B)Regional cardiac denervation alters SWOP in the[unreadable] remote, non-ischemic zone; C)SWOP results in enhanced long chain fatty acid (LCFA) oxidation during[unreadable] ischemia, potentially due to AMP kinase elevation, an effect which is abolished following SWOP in conscious[unreadable] pigs with regional cardiac denervation. Project 1 is tied closely to the other projects and cores, as well as to[unreadable] the major themes of the Program Project, which are: 1)Mechanisms of myocardial ischemia and reperfusion;[unreadable] 2)Molecular signaling; 3)Myocardial protection and cell survival vs. cell death; 4)lntegrative cardiovascular[unreadable] research. This project is also linked closely to Project 2, which also studies the chronically instrumented[unreadable] swine model, but in Project 2 the model is one of repetitive stunning (myocardial hibernation). Indeed,[unreadable] several of the aims are shared by Projects 1 and 2, since the two projects will address several of the same[unreadable] questions in the two different models. Project 1 interacts with Project 3 in terms of molecular signaling and[unreadable] mechanisms of apoptosis, and with Project 4 particularly related to H11 kinase, which will be administered to[unreadable] pigs with regional cardiac denervation, to determine if H11 kinase can restore protection after cardiac[unreadable] denervation. Project 1 also utilizes all of the Cores.[unreadable]